Reliance on the use of cytotoxic chemotherapeutic agents for treatment of HIV-associated lymphomas may not significantly prolong survival since these agents are difficult to deliver in the setting of poor myeloid reserve and they tend to exacerbate the underlying immunodeficiency state. The overall goal of this proposal is the identification of active new agents which are less immuno-and myelosuppressive than conventional chemotherapy for the treatment of HIV-associated non-Hodgkin's lymphomas. Since the use of single agents alone is unlikely to produce long-term remissions due to selection of resistant clones, the long term aim is to identify active agents and to ultimately use them in combination or sequentially with conventional cytotoxic therapy. This approach might minimize the intensity with which chemotherapy is administered. The objectives will be achieved by conducting prospective clinical trials of three novel approaches to the treatment of HIV-associated NHL: (1) A trial of ricin A-chain conjugated anti-CD22 in those individuals whose tumors are CD22 positive. (2) A trial of anti-idiotype monoclonal antibody therapy in those patients whose tumors express the appropriate cell-surface idiotype and (3) A combination of a recently identified active agent, 2'-chlorodeoxyadenosine (CdA), with the combination of etoposide and ifosfamide also recently identified as having activity in refractory HIV-NHL. In addition, subjects with primary central nervous system lymphoma will be treated with whole brain irradiation, antiretroviral therapy and Pneumocystis carinii prophylaxis therapy to determine whether survival can be prolonged, whether a significant proportion of patients die as a result of their lymphoma and, therefore, whether or not more aggressive approaches to the treatment of HIV-associated primary CNS lymphoma are warranted. Finally, prospective evaluation of the molecular characteristics of lymphomas from individuals receiving primary therapy will be correlated with clinical features to determine whether molecular features may play a role in decisions regarding therapeutic approach.